Mechanism of dysregulated myogenic dedifferentiation and growth of rhabdomyosarcoma cells

Supervisors:  Professor Tej Dhoot (TDhoot@RVC.AC.UK), Dr Abir Mukherjee (amukherjee@rvc.ac.uk)

Rhabdomyosarcoma is the most common paediatric soft tissue sarcoma accounting for 5-10% of childhood malignancies and a leading cause of cancer death [1]. There are two main subgroups of this cancer, embryonal and alveolar. The latter associated with gene fusions such as PAX3-FOXO1 or PAX7-FOXO1 generated by chromosomal translocations is relatively more aggressive. Most cancers sustain continuing growth through dysregulation of one or multiple signalling proteins [2]. A number of rhabdomyosarcomas have also been reported to activate multiple signalling pathways and are known to harbour mutations in the components of receptor tyrosine kinase signalling pathways [1,3].  We hypothesise that the inhibition of cell signalling pathways that promote cell proliferation at the expense of differentiation would inhibit tumour growth. The purpose of this project is to determine if candidate cell signalling inhibitors, including cell signalling modulators such as PI-88 (HS-mimetic) and/or Sulf1/Sulf2 [2] can inhibit tumour growth by enforcing cell differentiation. The aims of this project are:

1.    To analyse the nature of key cell signalling pathways driving tumour growth of a selected embryonal and alveolar rhabdomyosarcoma cell type.

2.    To determine if some cell signalling inhibitors such as AG1478 or Imatinib or  HSPG (heparan sulfate proteoglycan) co-receptor inhibitors such as PI-88 and si.Sulf1 or si.Sulf2 can inhibit the growth of such cells.

3.    To determine the mechanism of cell signalling inhibition by analysing cell proliferation versus multi-stage differentiation markers.

This project will involve the use of cell culture, RNA and cDNA preparation for RT- PCR analyses, immunocytochemistry and immunoblotting procedure to monitor changes in myogenic differentiation.

References:

1.    M. Ehnman et al 2013, Cancer Res. 73:2139-2149.

2.    R. Gill et al 2014, Exp. Cell Res. 324:157-171.

3.    S. Rossi et al 2011, Eur. J. Cancer, 47:1095-1105.

If you would like to apply for this studentship please contact the supervisors in the first instance and then apply via UKPASS. See also the How to Apply box

The deadline for applications is 3rd April 2016